Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.

com

186

STOMACH

Risk factors for peptic ulcer disease: a population based

prospective cohort study comprising 2416 Danish adults
S Rosenstock, T Jrgensen, O Bonnevie, L Andersen
.............................................................................................................................

Gut 2003;52:186193

See end of article for
authors affiliations tion period were verified through medical records. Information on psychosocial factors, lifestyle prac-
.......................
Correspondence to:
Dr S Rosenstock,
Department of Surgery
D26, Glostrup University
Hospital, Nordre Ringvej
2600 Glostrup, Denmark;
rosenstock.s@dadlnet.dk
Accepted for publication
3 September 2002
.......................
Background: No population based prospective cohort study has previously assessed the impact of
multiple risk factors, including Helicobacter pylori infection, on the incidence of peptic ulcer disease
(PUD).
Aims: To identify risk factors for PUD and estimate their relative impact on ulcer incidence.
Subjects: Random sample of 2416 Danish adults with no history of PU.
Methods: Sample members were interviewed in 1982 and 1994. PUs diagnosed within the observa-
tices, and medication was obtained from a questionnaire completed at study entry. H pylori infection
status was determined by ELISA.
Results: The main risk factors for PUD were H pylori infection (odds ratio 4.3 (95% confidence inter-
val 2.2; 8.3)), tobacco smoking (3.8 (1.7; 9.8)), and use of minor tranquillisers (3.0 (1.4; 6.6)). Intake
of non-steroid anti-inflammatory drugs did not affect the incidence of PUD (0.4 (0.1; 2.3)). In those with
increased antibodies to H pylori, tobacco smoking (12.7 (2.8; 56.8)) and intake of spirits (2.4 (1.1;
5.4)) increased the risk of PUD whereas moderate leisure time physical activity (0.3 (0.2; 0.7))
protected against PUD.
Conclusions: Tobacco smoking and H pylori infection are the main risk factors for PUD in Danish
adults. Physical activity may protect against PUD in those infected with H pylori.

A
lthough it is generally accepted that the aetiology of pep-
tic ulcer disease (PUD) is multifactorial, data on the
relative impact of single risk factors are scarce. A
number of population based prospective studies have been
published16 but so far no study has assessed the effect of
Helicobacter pylori infection together with other PUD determi-
nants. A meta-analysis suggested that 95% of all hospitalised
ulcer cases in the USA were attributable to H pylori infection,
use of non-steroidal anti-inflammatory drugs (NSAIDs), and
tobacco smoking.7 Hospitalised ulcer cases differ from uncom-
plicated ulcer cases in terms of aetiology and comorbidity.
Moreover, H pylori infection rates vary considerably between
continents.8 9 It is therefore likely that PU risk factors contrib-
ute differently to ulcer occurrence in general populations as
well as to ulcer occurrence in different parts of the world.10
The aims of this study were: firstly, to identify risk factors
for PUD and estimate their relative impact on ulcer incidence
in Denmark; and secondly, to identify possible interactions
between factors that relate to ulcer incidence.
MATERIALS AND METHODS
Study population
A random sample of 4581 Danish adults aged exactly 30, 40, 50,
and 60 years were invited to a population study in October
1982.11 A total of 3608 subjects (78.8%) accepted the invitation.
By January 1993, 451 members of the original sample had died
or disappeared. The remaining 4130 sample members were
invited to a follow up examination. A total of 2656 subjects
attended the follow up which took place between June 1993 and
December 1994.12 The Regional Research Ethics Committee of
Copenhagen County approved the project.
1982. In June 1993, all samples were thawed and analysed for
IgG antibodies (anti-Hp IgG) to H pylori. Blood samples drawn
at follow up (n=2541) were examined continuously. Match-
ing pairs of sera were identified in 2527 cases. A total of 2416
of these participants had no history of PUD when entering the
study and were eligible for the present study.
IgG antibodies directed against a low molecular weight
fraction of H pylori antigens were measured with a validated
inhouse indirect ELISA.1315 IgG antibody levels were categor-
ised as seronegative, borderline increased, or seropositive.
Sensitivity, specificity, positive predictive value, and negative
predictive value of the IgG serology assay were 98.5%, 54.0%,
76.1%, and 96.2%, respectively
Peptic ulcer diagnosis
All participants were asked if they had been diagnosed with a
peptic ulcer within the 11 year observation period. Participants
with a first time diagnosed ulcer reported how and when the
diagnosis was made. To ensure that all first time diagnosed
ulcers were recorded, information was also obtained from the
National Danish Hospital Discharge Registry (NDHDR) in
which all cases of hospital admissions in Denmark are
registered with a discharge diagnosis. The search included the
following PUD diagnoses (WHO ICD-8 codes: 531.X (gastric
ulcer), 532.X (duodenal ulcer), and 533.X (gastro-duodenal
ulcer)). Medical records from those who reported an ulcer or
who were registered with a PUD diagnosis in the NDHDR were
retrieved and reviewed. Only ulcers verified by upper endoscopy,
barium meal examination, or surgery were regarded as true
incident ulcers. Active ulcers were considered to be gastric
ulcers (GUs) when a crater with appreciable depth was seen in

Collection of sera and diagnosis of H pylori infection .............................................................

Large scale testing for antibodies to H pylori became available Abbreviations: PUD, peptic ulcer disease; NSAIDs, non-steroidal
in the beginning of the 1990s in Denmark. Blood samples had anti-inflammatory drugs; GU, gastric ulcer; DU, duodenal ulcer; PPI,
already been drawn from 3590 participants at study entry in proton pump inhibitor.

www.gutjnl.com
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com

Risk factors for peptic ulcer disease 187

Table 1 Eleven year cumulated incidence of peptic ulcer disease (PUD) in 1994 by
categories of baseline exposures: Helicobacter pylori infection and lifestyle practices.
Unadjusted and sex and age adjusted odds ratios (OR, 95% confidence intervals (CI))
PUD incidence Unadjusted Sex and age adjusted
Baseline exposure
(reference category) % n Odds ratio 95% CI Odds ratio 95% CI

Anti-Hp IgG sero-status

(Seronegative) 1.3 1412 1.0 1.0
Borderline 5.7 456 4.7 2.5;8.6 4.5 2.4;8.3
Seropositive 4.7 548 3.9 3.9;7.1 3.6 1.9;6.7
Anti-Hp changes within the observation period
(Persistently seronegative) 1.1 1286 1.0 1.0
Persistently borderline 3.0 305 2.8 1.2;6.4 2.7 1.1;6.3
Persistently seropositive 4.1 459 3.9 2.0;7.9 3.7 1.8;7.6
Changes in anti-Hp infection status 5.0 343 4.7 2.3;9.7 4.6 2.2;9.5
Cumulative tobacco consumption
(Never smoker) 1.0 691 1.0 1.0
Former smoker 2.1 482 2.1 0.8;5.5 2.1 0.8;5.6
114.99 g/day 4.0 596 4.1 1.8;9.6 4.4 1.9;10.3
1524.99 g/day 4.3 535 4.4 1.8;10.2 5.1 2.1;12.0
>25 g/day 4.8 126 4.9 1.6;14.8 5.9 1.8;18.0
Cumulative number of cigarettes smoked daily*
(0) 1.9 996 1.0 1.0
19 cigarettes 2.7 374 1.4 0.7;3.1 1.5 0.7;3.2
1014 cigarettes 2.7 369 1.4 0.7;3.1 1.6 0.7;3.5
1520 cigarettes 5.0 556 2.1 1.1;3.9 2.4 1.3;4.5
>21 cigarettes 6.7 135 3.7 1.6;8.3 4.3 1.9;9.9
Wine (weekly consumption)
(Never drink wine) 4.2 690 1.0 1.0
13 glasses of wine 2.2 1112 0.5 0.3;0.9 0.5 0.3;0.9
> 4 glasses of wine 2.7 628 0.6 0.3;1.2 0.6 0.3;1.2
Spirits (weekly consumption)
(Never drink spirits) 2.8 1275 1.0 1.0
12 glasses of spirits 2.7 784 0.9 0.6;1.6 0.9 0.5;1.6
>3 glasses of spirits 3.5 371 1.3 0.7;2.4 1.2 0.6;2.3
Beer (weekly consumption)
(Never drink beer) 3.4 711 1.0 1.0
12 beers 2.8 703 0.8 0.5;1.5 0.8 0.4;1.6
36 beers 2.0 503 0.6 0.3;1.2 0.6 0.3;1.3
710 beeers 2.2 223 0.7 0.2;1.7 0.6 0.2;1.8
>11 beers 3.8 290 1.1 0.5;2.3 1.1 0.5;2.6
Cumulative number of drinks (weekly consumption)
(02 drinks) 3.4 670 1.0 1.0
35 drinks 2.8 567 0.8 0.4;1.6 0.8 0.4;1.6
612 drinks 1.7 650 0.5 0.2;1.0 0.5 0.2;1.0
>13 drinks 3.7 549 1.1 0.6;2.0 1.1 0.5;2.6
Tea (cups taken daily)
(0) 3.2 1240 1.0 1.0
12 2.5 671 0.8 0.4;1.4 0.8 0.4;1.4
>3 2.5 519 0.8 0.4;1.5 0.8 0.4;1.5
Coffee (cups taken daily)
(03) 2.9 732 1.0 1.0
45 2.1 621 0.7 0.4;1.5 0.7 0.4;1.4
68 2.8 679 1.0 0.5;1.8 1.0 0.5;1.8
>9 4.3 398 1.5 0.8;2.9 1.6 0.8;3.0
Leisure time energy expenditure
(Sedentary) 4.4 589 1.0 1.0
Ambulatory 2.3 1294 0.5 0.3;0.9 0.5 0.3;0.9
Active 2.6 547 0.6 0.3;1.1 0.5 0.3;1.1

Data for cigar, cheroot, and pipe smokers are not shown as there were very few ulcer cases in these subgroups.
*In former and current smokers.

the fundus, corpus, or antrum area. Craters in the pyloric canal
or in the duodenum were classified as duodenal ulcers (DUs).
Scars or deformities were accepted as signs of former ulcers.
Malignant ulcers were excluded.
Study variables
A self administered questionnaire was completed at both
attendances. The following variables were assessed:
(i) sociodemographic factors: sex, age;
(ii) socioeconomic status16;
(iii) genetic factors: family history of PUD, Lewis blood group
antigens;
(iv) lifestyle practices: tobacco smoking (cumulative tobacco
consumption (g/day)cumulative consumption of different
tobacco products), alcohol (weekly consumption of beer, wine,
and spiritscumulative weekly number of drinks), coffee and
tea intake (number of cups taken daily), leisure time physical
activity (sedentary, ambulatory, active);
(v) medication assessed at study entry: unspecified drugs for
gastrointestinal disorders, unspecified antirheumatic drugs
(NSAIDs), minor and major tranquillisers, antibiotics;
(vi) medication assessed at follow up: antacids, H2 receptor
antagonists, proton pump inhibitors (PPIs), ASA, acetamino-
phen, NSAIDs, and antibiotics.
Use of medications was categorised as never-infrequent,
previous use within the past five years (daily, weekly, monthly,
prophylactic treatment regimens), or current use (daily,

www.gutjnl.com
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com

188 Rosenstock, Jrgensen, Bonnevie, et al

Table 2 Eleven year cumulated incidence of peptic ulcer disease (PUD) in 1994 by
categories of baseline exposures: medication at study entry and five years preceding
follow up. Unadjusted and sex and age adjusted odds ratios (OR, 95% confidence
intervals (CI))
PUD incidence Unadjusted Sex and age adjusted
Baseline exposure
(reference category) % n Odds ratio 95% CI Odds ratio 95% CI

Uspecified gastrointestinal drugs in 1982

(Never-infrequent use) 2.4 2071 1.0 1.0
Previous use 2.4 125 1.0 0.3;3.2 1.2 0.4;4.0
Current use 7.3 232 3.2 1.8;5.6 3.2 1.7;5.5
Antirheumatic drug use at study entry in 1982
(Never-infrequent use) 2.9 2156 1.0 1.0
Previous use 2.6 190 0.9 0.4;2.3 0.9 0.3;2.2
Current use 2.4 82 0.8 0.2;3.5 0.7 0.2;3.0
Antibiotic use at study entry in 1982
(Never-infrequent use) 2.8 2402 1.0 1.0
Previous use 0.0 8
Current use 11.1 18 4.1 0.9;18.1 4.2 1.1;16.9
Major tranquilliser use at study entry in 1982
(Never-infrequent use) 2.4 2381 1.0 1.0
Previous use 0.0 1
Current use 2.0 37 2.3 0.5;9.9 2.2 0.5;9.6
Minor tranquilliser use at study entry in 1982
(Never-infrequent use) 2.1 2373 1.0 1.0
Previous use 3.6 28 1.7 0.2;12.9 1.8 0.2;13.4
Current use 8.5 118 4.3 2.1;8.7 4.4 2.1;9.2
Antacid use in the past 5 years
(Never-infrequent use) 2.3 2367 1.0 1.0
Previous use 9.5 21 4.4 1.0;19.5 4.1 0.9;18.2
Current use 6.5 31 2.9 0.7;12.5 2.8 0.7;12.3
H2 receptor antagonist use in the past 5 years
(Never-infrequent use) 1.7 2371 1.0 1.0
Previous use 34.6 26 30.1 12.7;71.5 30.5 12.6;74.0
Current use 40.9 22 39.3 15.9;97.2 38.6 15.4;97.2
Proton pump inhibitor use in the past 5 years
(Never-infrequent use) 2.2 2397 1.0 1.0
Previous use 33.3 9 22.1 5.4;90.9 20.1 4.8;83.9
Current use 30.0 10 19.0 4.8;75.4 16.6 4.1;67.0
NSAID use in the past 5 years
(Never-infrequent use) 2.5 2256 1.0 1.0
Previous use 0.0 33
Current use 2.3 130 0.9 0.3;3.0 0.9 0.3;3.0
ASA use in the past 5 years
(Never-infrequent use) 2.4 2305 1.0 1.0
Previous use 0.0 1
Current use 2.7 113 1.1 0.3;3.6 0.9 0.3;3.1
Paracetamol use in the past 5 years
(Never-infrequent use) 2.3 2159 1.0 1.0
Previous use 0.0 9
Current use 4.0 251 1.8 0.9;3.6 1.8 0.9;3.7
Antibiotic use in the past 5 years
(Never-infrequent use) 2.4 2390 1.0 1.0
Previous use 0.0 1
Current use 7.4 27 3.3 0.8;14.2 3.2 0.7;13.7

Medication: previous or current daily, weekly, or monthly use. Blank cells indicate missing data or that
numbers do not allow inferences.

weekly, monthly, prophylactic treatment regimens). H pylori
infection status was assessed as anti-Hp IgG status at study
entry and follow up, and as changes in anti-Hp IgG status
within the observation period.
Statistical methods
The SPSS statistical package for Windows was used.17 The
incidence of PUD was used as the dependent variable in a
series of logistic regression analyses using forward stepwise
inclusion. All variables that improved the fit of sex and age
adjusted models were incorporated into a final logistic
regression model together with possible confounders (multi-
variate adjusted ORs). As some variables were interrelated,
different final models were constructed. Exposure status at
study entry (baseline exposure status) was assumed to reflect
risk factor exposure at the time of ulcer diagnosis.
Interaction terms were fitted into the analyses if effect
modification was suspected. If effect modification was
demonstrated, separate analyses were made for each
stratumfor example, anti-Hp positive/borderline and anti-
Hp negative participants.
The population attributable risk per cent (PAR%) was
calculated from the following equation:
PAR% = (Pe (OR1)/Pe (OR1) + 1) 100
where Pe is the prevalence of the exposure at baseline and OR
is the multivariate adjusted risk of PUD.18 Level of significance
was set at 5%.
RESULTS
Response patterns at follow up
Members of the original cohort who failed to attend the follow
up examination (non-responders) differed from those who
attended follow up (responders) by being older (odds ratio 2.7

www.gutjnl.com
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com

Risk factors for peptic ulcer disease 189

perforated ulcers were found at surgery, and four ulcers were

Table 3 Final logistic regression model for all ulcers. verified by a combination of different diagnostic methods.
Helicobacter pylori infection, lifestyle practices, and
medication at study entry (odds ratios and 95% H pylori infection at baseline and follow up
confidence intervals)* Seropositive or borderline increased anti-Hp IgG levels at
Multivariate adjusted study entry significantly increased the likelihood of develop-
Baseline exposure ing an ulcer (table 1). There were no cases of PUD among
(reference category) Odds ratio 95% CI patients who became infected with H pylori within the
Anti-Hp IgG sero-status observation period (n=14) but those who had a fourfold
(Seronegative) 1.0 decrease in baseline anti-Hp IgG levels suggesting loss of the
Borderline 3.4 1.8;7.3 infection (n=44) were more likely than those who remained
Seropositive 4.3 2.2;8,3
seropositive to report an ulcer. A high number of PUD cases
Anti-Hp changes within the observation period
(Persistently seronegative) 1.0 was seen in those who showed variations in antibody status
Persistently borderline 2.2 0.9;5.3 (table 1).
Persistently seropositive 3.6 1.8;7.4 Fifty two (74.3%) ulcers were diagnosed in patients with
Changes 4.8 2.3;10,0 seropositive or borderline increased anti-Hp IgG whereas the
Cumulative tobacco consumption
remaining 18 ulcers (25.7%) were seen in IgG seronegative
(Never-smoker) 1.0
Former smoker 2.0 0.7;5.9 individuals. The seroprevalence of H pylori infection was 87.2%
114.99 g/day 4.0 1.6;10.4 in DU (IgG seropositive 56.4%/IgG borderline 30.8%) and 60.0%
1524.99 g/day 4.5 1.6;11.0 in GU patients (IgG seropositive 13.3%/IgG borderline 46.7%).
>25 g/day 3.0 0.8;11.9
Cumulative number of cigarettes smoked daily Lifestyle practices at baseline
0 1.0
Tobacco smoking caused a significant increase in the risk of
19 cigarettes 1.5 0.6;3.5
1014 cigarettes 1.3 0.5;3.1 developing an ulcer (table 1). Dose-response relationships
1520 cigarettes 2.0 1.0;4.1 were seen between PU incidence and cumulative tobacco con-
>21 cigarettes 2.5 0.9;6.9 sumption and cumulative number of cigarettes. The low
Wine (weekly consumption) number of ulcers among users of other tobacco products did
(Never drink wine) 1.0
not allow separate analyses.
13 glasses of wine 0.5 0.3;1.2
>4 glasses of wine 0.6 0.2;1.3 A tendency towards an increase in the PUD incidence pro-
Spirits (weekly consumption) portion with the number of consumed drinks was observed
(Never drink spirits) 1.0 resulting in a U shaped relation. The nadir of the
12 glasses of spirits 1.8 0.9;3.6 distribution was 612 drinks weekly. This relationship was
>3 glasses of spirits 1.8 0.8;4.3
due to a low number of ulcers among people who drank mod-
Cumulated number of drinks (weekly consumption)
(02 drinks) 1.0 erate amounts of wine. Intake of beer and spirits did not affect
35 drinks 1.2 0.6;2.5 the overall ulcer incidence proportion.
612 drinks 0.5 0.2;1.1 Although a high number of PUD cases was reported in
>13 drinks 0.9 0.4;1.8 patients who consumed large amounts of coffee, ulcer
Leisure time energy expenditure
incidence in general did not relate to the use of coffee and tea
(Sedentary) 1.0
Ambulatory 0.5 0.3;0.9 at study entry. A possible protective effect of moderate to high
Active 0.8 0.4;1.6 leisure time energy expenditure against PUD was seen.
Uspecified gastrointestinal drugs at study entry in 1982
(Never-infrequent use) 1.0 Drug consumption
Previous use 1.2 0.4;4.3 Drug consumption at study entry
Current use 3.2 1.7;6.2
NSAID use at study entry in 1982
Current use of antibiotics, unspecified gastrointestinal drugs,
(Never-infrequent use) 1.0 and minor tranquillisers was associated with high ulcer
Previous use 0.8 0.3;2.3 incidence rates at follow up (table 2). The use of antirheumatic
Current use 0.4 0.1;2.3 drugs did not relate to ulcer incidence.
Minor tranquillisers use at study entry in 1982
(Never-infrequent use) 1.0
Previous use 1.9 0.2;15.0 Drug consumption at follow up
Current use 3.0 1.4;6.6 As could be expected, the use of antacids, H2 receptor antago-
nists, and PPIs was more frequent among those who had a
*Different logistic regression models were constructed as some variables
were inter-related and could not be fitted into the same model.
first time diagnosed peptic ulcer.
In former and current smokers.
Medication: daily, weekly, or monthly previous or current use. Multivariate logistic regression analyses
In addition to the variables in question, all final models were
controlled for demographic, psychosocial, and genetic factors.
(95% confidence interval 2.2; 3.4)), by emanating from poor
socioeconomic strata (1.9 (1.4; 2.4)), by being heavy smokers Final model for all ulcers
(2.4 (1.9; 3.0)), and by being psychologically vulnerable (1.5 To preserve statistical power regression analyses were initially
(1.2; 2.0)). H pylori infection status did not affect the response done for all ulcers together. The following baseline exposures
pattern. were associated with an increased risk of reporting a PU at
follow up: seropositive or borderline increased anti-Hp IgG,
Peptic ulcer incidence and diagnostic verification tobacco smoking, current use of minor tranquillisers, and cur-
A total of 71 first time diagnosed ulcers were eligible for rent use of unspecified gastrointestinal drugs (table 3). The
analyses. The 11 year cumulative incidence proportion was dose-response relationship between cumulative tobacco con-
2.9% (95% confidence interval 2.2; 3.6)that is, 1.6% (1.1; sumption and PU incidence persisted in multivariate analyses.
2.1), 1.3% (0.8; 1.7), and 0.04% (0.02; 0.07) for DU (n=39), GU Moderate leisure time energy expenditure reduced the
(n=31), and combined ulcers (n=1), respectively. Sixteen likelihood of PUD. Regression models, which included differ-
ulcers had been verified by barium meal examination, 45 ent alcohol containing beverages instead of cumulative
ulcers were diagnosed by upper endoscopy, five cases of number of drinks, did not yield further information. No other

www.gutjnl.com
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com

190 Rosenstock, Jrgensen, Bonnevie, et al

Table 4 Final logistic regression model for anti-Hp IgG seropositive/borderline participants and for duodenal ulcer
disease. Eleven year cumulated incidence of peptic ulcer disease (PUD). Odds ratios and 95% confidence intervals (CI)*
Anti-Hp IgG positive or borderline participants Duodenal ulcer

PUD incidence Multivariate adjusted* PUD incidence Multivariate adjusted*

Baseline exposure
(reference category) % n Odds ratio 95% CI % n Odds ratio 95% CI

Anti-Hp IgG sero-status

(Seronegative) 0.4 1400 1.0
Borderline 2.7 442 6.0 1.7;20.1
Seropositive 4.0 544 16.0 5.2;49.3
Cumulative tobacco consumption
(Never-smoker) 1.1 270 1.0
Former smoker 3.1 225 4.0 0.8;20.8
114.99 g/day 9.6 239 12.7 2.8;56.8
1524.99 g/day 7.9 215 8.5 0.4;25.1
>25 g/day 3.6 55 3.2 0.8;11.9
Cumulative number of cigarettes smoked daily
0 2.7 403 1.0 0.6 975 1.0
19 cigarettes 5.4 168 2.4 0.9;6.4 1.4 368 2.6 0.7;9.2
1014 cigarettes 6.8 148 2.3 0.9;6.4 2.2 364 3.6 1.1;12.1
1520 cigarettes 7.6 224 2.9 1.2;6.8 2.9 548 5.0 1.8;14.4
>21 cigarettes 8.2 61 2.5 0.7;9.0 3.8 131 7.7 2.0;29.0
Wine (weekly consumption)
(Never drink wine) 7.2 335 1.0 2.5 676 1.0
13 glasses of wine 3.6 440 0.5 0.2;1.2 1.4 1099 0.5 0.2;1.2
>4 glasses of wine 5.2 229 0.6 0.3;1.5 1.3 611 0.4 0.1;1.2
Spirits (weekly consumption)
(Never drink spirits) 4.8 547 1.0 1.5 1251 1.0
12 glasses of spirits 5.1 311 2.4 1.1;5.4 1.6 770 1.7 0.8;4.0
>3 glasses of spirits 6.8 146 1.8 0.7;4.4 2.5 365 1.7 0.7;4.6
Leisure time energy expenditure
(Sedentary) 8.8 239 1.0 2.4 574 1.0
Ambulatory 4.0 524 0.3 0.2;0.7 1.4 1273 0.8 0.4;1.8
Active 4.1 241 0.6 0.2;1.4 1.5 539 1.2 0.4;3.2
Uspecified gastrointestinal drugs at study
entry
(Never-infrequent use) 4.4 856 1.0 1.4 2037 1.0
Previous use 4.5 44 1.3 0.3;6.0 0.8 123 0.5 0.1;4.2
Current use 11.7 103 3.0 1.4;6.5 4.5 224 3.4 1.5;7.4
Minor tranquilliser use at study entry in 1982
(Never-infrequent use) 3.9 924 1.0 _ 1.4 2212 1.0
Previous use 5.9 17 2.9 0.3;24.9 0.0 27 0.1
Current use 12.7 55 2.8 1.1;7.3 4.5 107 2.6 0.8;7.5

*All odds ratios are mutually adjusted and adjusted for age, sex, and psychosocial factors.
All duodenal ulcer patients were former or current smokers.
Blank cells indicate that the variable was inapplicable.

factors including age, sex, genetic factors, and NSAID intake ment in this subgroup. An insignificant protective effect of
were shown to affect PUD incidence proportions. wine drinking on ulcer development was noted.

Effect modification Final model for anti-Hp seronegative individuals

A significant effect modification was demonstrated between H
pylori status and tobacco smoking (odds ratio 70.9) suggesting
that smoking only affects ulcer diathesis in patients infected
with H pylori. A six point ordinal variable that combined tobacco
smoking and anti-Hp IgG status was constructed. Patients who
were current tobacco smokers at study entry and had increased
IgG antibodies to H pylori (seropositive or borderline) suffered
an almost sevenfold increased risk of developing an ulcer com-
pared with anti-Hp negative never smokers (odds ratio 6.6 (95%
confidence interval 2.3; 19.0)). No other significant interactions
could be demonstrated. To account for this effect, modification
stratum specific analyses by H pylori infection status were done.
Final model for anti-Hp seropositive and borderline
individuals
Tobacco smoking, weekly consumption of spirits, and use of
unspecified gastrointestinal drugs or minor tranquillisers at
study entry were associated with higher PUD incidence rates
in those with seropositive or borderline increased IgG
antibodies to H pylori (table 4). In contrast, moderate leisure
time physical activity seemed to protect against ulcer develop-
Only 18 H pylori seronegative ulcers were available for
analyses. Although tobacco smoking, use of minor tranquil-
lisers, and tea consumption were related to PUD incidence in
this subgroup, none of these associations reached significance.
Final model for duodenal ulcers
All duodenal ulcer patients were either former smokers or
current smokers. Among former and current smokers there
was a marked dose-response relationship between the
number of cigarettes smoked daily and DU incidence (table 4).
Increased anti-Hp IgG levels and use of unspecified gastro-
intestinal drugs at study entry were associated with an
increase in the likelihood of developing a DU within the
observation period.
Final model for gastric ulcers
Borderline increased IgG antibodies to H pylori and use of
minor tranquillisers at study entry increased the odds of hav-
ing a gastric ulcer whereas leisure time energy expenditure
seemed to reduce gastric ulcer risk (table 5). The use of
NSAIDs did not increase the risk of GU.

www.gutjnl.com
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com

Risk factors for peptic ulcer disease 191

Table 5 Final logistic regression model for gastric ulcer disease; 11 year cumulative
incidence of peptic ulcer disease (PUD). Odds ratios and 95% confidence intervals
(CI)*
Gastric ulcer

PUD incidence Multivariate adjusted*

Baseline exposure (reference category) % n Odds ratio 95% CI

Anti-Hp IgG sero-status

(Seronegative) 0.9 1407 1.0
Borderline 3.2 444 2.7 1.2;6.6
Seropositive 0.8 526 0.7 0.2;2.4
Leisure time energy expenditure
(Sedentary) 2.1 572 1.0
Ambulatory 1.0 1268 0.4 0.1;0.9
Active 1.1 537 0.7 0.2;2.1
Uspecified gastrointestinal drugs at study entry
(Never-infrequent use) 1.0 2029 1.0
Previous use 1.6 124 2.1 0.5;10.0
Current use 3.6 222 3.0 1.1;8.1
Minor tranquilliser use at study entry
(Never-infrequent use) 0.8 223 1.0
Previous use 3.6 28 4.0 0.5;32.5
Current use 4.5 112 3.4 1.2;10.0
NSAID use at study entry
(Never-infrequent use) 1.4 2079 1.0
Previous use 0.5 185 0.4 0.1;2.8
Current use 1.2 80 0.7 0.1;6.0

*All odds ratios are mutually adjusted and adjusted for age, sex, and psychosocial factors.

Table 6 Population attributable risk per cent (PAR%) for different risk factors for
peptic ulcer disease (PUD) in 2416 Danish adults with no previous history of ulcer
disease
Variable (baseline exposure) Pe* Odds ratio PAR%

Seropositive for IgG antibodies to H pylori 0.24 4.3 44.2

Current tobacco smoking 0.56 3.8 61.0
Poor socioeconomic status 0.12 2.9 18.4
Current use of minor tranquillisers 0.06 2.4 8.2

*Prevalence of exposure to variable at study entry.

Multivariate adjusted odds ratios. Odds ratios for H pylori infection, tobacco smoking, and medication are
reported elsewhere.

Aetiological fractions usually overestimates the prevalence of active H pylori

Table 6 shows the attributable risk per cents for baseline expo-
sures that were shown to increase the risk of first time
diagnosed PUs significantly, irrespective of ulcer site. Because
of a high prevalence of tobacco smoking, smoking accounted
for more than 60% of all ulcer cases in this cohort whereas
44% of ulcer cases were attributable to H pylori infection. The
remaining risk factors accounted for approximately 25% of the
variance.
DISCUSSION
Ours is one of the first population based prospective studies in
the H pylori era which has examined the impact of several risk
factors for PUD, including H pylori. The most important find-
ings were that H pylori infection, tobacco smoking, and use of
minor tranquillisers were the main risk factors for PUD in this
population of Danish adults. Leisure time energy expenditure
reduced the likelihood of PUD. When analyses were confined
to H pylori positive individuals, wine drinking showed a possi-
ble protective effect against PUD whereas intake of spirits
increased ulcer risk. Use of NSAIDs did not affect GU or DU
rates. A significant effect modification was demonstrated
between tobacco smoking and H pylori infection, suggesting
that tobacco smoking only increases PU risk in those who
harbour H pylori.
Approximately 25% of all incident ulcers were found in
those with no serological signs of H pylori infection. Serology
infection. The serology used in this study measures low
molecular weight H pylori antigens that are less strongly
expressed in patients with gastric atrophy. The prevalence of
infection may therefore be slightly underestimated in older
people. The low specificity of the serology implies a high
number of anti-Hp false positive results. This misclassification
weakens the impact of H pylori infection on ulcer incidence. As
the prevalence of H pylori infection is low in Denmark,19 the
proportion of ulcers that can be attributed to H pylori infection
is likely to be higher in countries where H pylori infection is
more common.
In contrast with data from the USA,7 tobacco smoking
seems to be a more important risk factor for PUD than H pylori
infection in Denmark.20 21 Recent studies have suggested that
tobacco smoking causes PU only if H pylori infection is
present.2224 Our findings support this notion but tobacco
smoking remained an independent risk factor for PUD despite
control for H pylori infection status. For that reason, we believe
that ulcer patients should be advised to cease smoking
irrespective of H pylori infection status.25
The association between coffee drinking and PUD is
controversial.26 The prospective nature of this study should
prevent bias resulting from changes in coffee drinking habits
due to medical advice.27 28 Still, it is possible that ulcer patients
may have reduced their coffee intake prior to ulcer diagnosis
because of abdominal discomfort.

www.gutjnl.com
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com
192
Recent studies have shown a significant reduction in
duodenal ulcer risk in American men who exercise
regularly.29 Older studies suggest that physical inactivity
increases the likelihood of ulcer disease.30 31 Moderate energy
expenditure was shown to reduce the overall likelihood of
ulcer disease in this study. Possible mechanisms could include
a decrease in gastric acid secretion, lower levels of stress, and
differences in dietary factors.32
H pylori infection rates in DU disease are declining.33 34 The
seroprevalence of H pylori infection was 87.2% in DU patients
when those with borderline increased anti-Hp IgG were
considered infected. This value overestimates the true
prevalence as some patients with borderline increased IgG
antibodies are uninfected. When this subgroup was excluded,
the seroprevalence of H pylori infection was 56.4% in DU
patients and even lower in GU patients. The present data
therefore support the notion that the prevalence of H pylori
infection in DU patients is lower than previously thought and
emphasises that eradication therapy should not be initiated
without prior verification of the infection.35
The absence of an association between the use of NSAIDs
and PUD incidence is surprising. The link between PUD and
NSAID consumption is most pronounced in elderly patients
who present with bleeding GUs. Possible explanations for our
findings may be limited statistical power due to a low number
of first time diagnosed GUs, few complicated ulcers, a
relatively young cohort whose maximum age was 70 years, or
invalid data on the use of NSAIDs at study entry. It is also pos-
sible that the impact of NSAIDs could be less marked in the
general population who primarily suffers from uncomplicated
ulcers.
Although the present analyses were adjusted for psycho-
logical vulnerability, the relationship between minor tranquil-
lisers and ulcer incidence could simply be explained by differ-
ences in personality traits between ulcer patients and other
subjects.36 PUD was previously considered a psychosomatic
disease and tranquillisers may have been used to treat ulcer
patients. As more effective treatments have become available
within the last 20 years, this approach is unlikely to explain
the present findings.
In this study, inferences were made between baseline expo-
sure to possible risk factors and the subsequent development
of a peptic ulcer. No data were available on whether the
participant was exposed to the risk factor in question at the
time of ulcer formation. Although most patients retain their
lifestyle habits until disease develops, it is likely that some
may have ceased risk factor behaviour during the observation
period while others may have been exposed to a possible risk
factor not reported at study entry. This non-differential
misclassification will weaken possible relationships.
Moderate alcohol intake may reduce the likelihood of ulcer
disease3 32 37 38 but large scale population based studies have
failed to confirm this association.4 5 Intake of spirits increased
the risk of PU in patients with increased anti-Hp IgG in this
study. Excessive alcohol consumption has been shown to
increase the risk of PUD.39 Wine and beer drinking is
associated with lower rates of H pylori infection.38 40 41 Biologi-
cal mechanisms that could explain a possible beneficial effect
of wine drinking on H pylori infection and ulcer formation
have been reported.42 43 Wine drinking could also be a marker
for an overall healthier lifestyle.44
In conclusion, the aetiology of PUD is multifactorial.
Tobacco smoking, H pylori infection, and use of minor
tranquillisers but not NSAIDs are the main determinants to
PUD in this cohort of Danish adults. Alcohol containing bev-
erages in general did not relate to PUD incidence but intake of
spirits was shown to increase the risk of PU in patients with
increased anti-Hp IgG. Physical activity on the other hand
reduced the risk of PUD in this subgroup.
www.gutjnl.com
Rosenstock, Jrgensen, Bonnevie, et al
ACKNOWLEDGEMENTS
This study was supported by the Ingeborg Roikjer Foundation (9043),
the Danish Health Insurance Foundation (11/099-95), the Danish
Medical research Council (12-1844-1), the Else and Mogens
Wedell-Wedellsborg Foundation (6686-1), and the Jakob and Olga
Madsen Foundation.
.....................
Authors affiliations
S Rosenstock, T Jrgensen, Copenhagen County Centre for Preventive
Medicine, Glostrup University Hospital, Building 8.7. Nordre Ringvej, DK
2600 Glostrup, Denmark
O Bonnevie, Department of Medicine I, Bispebjerg Hospital, Bispebjerg
Bakke 23, DK 2400, Copenhagen, Denmark
L Andersen, Department of Infectious Hygiene 5222, Rigshospitalet,
Blegdamsvej 3, DK 2100, Copenhagen, Denmark
REFERENCES
1 Anda RF, Williamson DF, Escobedo LG, et al. Self-perceived stress and
the risk of peptic ulcer disease. A longitudinal study of US adults. Arch
Intern Med 1992;152:82933.
2 Everhart JE, Byrd-Holt D, Sonnenberg A. Incidence and risk factors for
self-reported peptic ulcer disease in the United States. Am J Epidemiol
1998;147:52936.
3 Cheng Y, Macera CA, Davis DR, et al. Does physical activity reduce the
risk of developing peptic ulcers? Br J Sports Med 2000;34:11621.
4 Johnsen R, Frde OH, Straume G, et al. Aetiology of peptic ulcer: a
prospective population study in Norway. J Epidemiol Community Health
1994;48:15660.
5 Kato I, Nomura AMY, Stemmermann GN, et al. A prospective study of
gastric and duodenal ulcer and its relation to smoking, alcohol and diet.
Am J Epidemiol 1992;135:52130.
6 Aldoori WH, Giovannucci EL, Stampfer MJ, et al. A prospective study of
alcohol, smoking, caffeine, and the risk of duodenal ulcer in men.
Epidemiology 1997;8:4204.
7 Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer.
Nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J
Clin Gastroenterol 1997;24:217.
8 Mgraud F, Brassens-Rabb M-P, Denis F, et al. Seroepidemiology of
Campylobacter pylori infection in various populations. J Clin Microbiol
1989;27:18703.
9 Graham DY, Malaty HM, Go MF. Are there susceptible hosts to
Helicobacter pylori infection? Scand J Gastroenterol 1994;29(suppl
205):610.
10 Schlemper RJ, Van Der Werf SDJ, Vandenbroucke JP, et al. Risk factors
of peptic ulcer disease: Different impact of Helicobacter pylori in Dutch
and Japanese populations? J Gastroenterol Hepatol 1996;11:82531.
11 Rosenstock SJ, Jrgensen T. Prevalence and incidence of peptic ulcer
disease in a Danish countya prospective cohort study. Gut
1995;36:81924.
12 Rosenstock SJ, Jrgensen T, Andersen LP, et al. Seroconversion and
seroreversion in IgG antibodies to Helicobacter pylori: a serology based
prospective cohort study. J Epidemiol Community Health
2000;54:44450.
13 Andersen LP, Raskov H-H, Elsborg L, et al. Prevalence of antibodies
against heat-stable antigens from Helicobacter pylori in patients with
dyspeptic symptoms and normal persons. APMIS 1992;100:77989.
14 Andersen LP, Espersen F, Souckova A, et al. Isolation and preliminary
evaluation of a low molecular (LMW) antigen preparation for improved
detection of Helicobacter pylori IgG antibodies. Clin Diagnostic Lab
Immunol 1995;2:1569.
15 Andersen LP, Kiilerich S, Pedersen G, et al. An analysis of seven
different methods to diagnose Helicobacter pylori infections. Scand J
Gastroenterol 1998;33:2430.
16 Hansen H. Living conditions in Denmark. Compendium of statistics.
Copenhagen: Danmarks Statistik, 1984.
17 Norusis MJ. SPSS for Windows. Advanced statistics release 6.0.
Chicago: SPSS Inc, 1993:230.
18 Hennekens CH, Buring JE. Epidemiology in medicine. Boston/Toronto:
Little, Brown and Company, 1987.
19 Andersen LP, Rosenstock SJ, Bonnevie O, et al. Seroprevalence of
immunoglobulin G, M, and A antibodies to Helicobacter pylori in an
unselected Danish population. Am J Epidemiol 1996;143:115764.
20 Andersen IB, Jrgensen T, Bonnevie O, et al. Smoking and alcohol
intake as risk factors for bleeding and perforated peptic ulcers: a
population-based cohort study. Epidemiology 2000;11:4349.
21 Kirchhoff M, Hansen B. Changes in smoking habits in a Danish
population from 1983 to 1988 (abstract in English). Ugeskr Lger
1995;157:345761.
22 Chan FKL, Sung JJY, Lee YT, et al. Does smoking predispose to peptic
ulcer relapse after eradication of Helicobacter pylori? Am J Gastroenterol
1997;92:4425.
23 Borody T, George L, Brandl S, et al. Smoking does not contribute to
duodenal ulcer relapse after Helicobacter pylori eradication. Am J
Gastroenterol 1992;87:13903.
24 Stack WA, Atherton JC, Hawkey GM, et al. Interactions between
Helicobacter pylori and other risk factors for peptic ulcer bleeding.
Aliment Pharmacol Ther 2002;16:497506.
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com
Risk factors for peptic ulcer disease
25 Parasher G, Eastwood GL. Smoking and peptic ulcer in the Helicobacter
pylori era. Eur J Gastroenterol Hepatol 2000;12:84353.
26 Suadicani P, Hein HO, Gyntelberg F. Genetic and life-style determinants
of peptic ulcer. A study of 3387 men aged 54 to 74 years: The
Copenhagen Male Study. Scand J Gastroenterol 1999;34:1217.
27 Eisig JN, Zaterka S, Massuda HK, et al. Coffee drinking in patients with
duodenal ulcer and a control population. Scand J Gastroenterol
1989;24:7968.
28 Kang JY, Tay HH, Guan R. Chronic upper abdominal pain: site and
radiation in various structural and functional disorders and the effect of
various foods. Gut 1992;33:7438.
29 Cheng Y, Macera CA, Blair SN. Physical acitivity and peptic ulcers.
Does physical activity reduce the risk of developing peptic ulcers? West J
Med 2000;173:1017.
30 Paffenberger RS, Wing AL, Hyde RT. Chronic disease in former college
students XIII. Early precursors of peptic ulcer. Am J Epidemiol
1974;100:39715.
31 Chuong JJH, Fisher RL, Chuong RLB, et al. Incidence, risk factors, and
predictive value of plasma pepsinogen. Dig Dis Sci 1986;31:117884.
32 Aldoori WH, Giovannucci EL, Stampfer MJ, et al. Prospective study of
diet and the risk of duodenal ulcer in men. Am J Epidemiol
1997;145:4250.
33 Ciociola AA, McSorley DJ, Turner K, et al. Helicobacter pylori infection
rates in duodenal ulcer patients in the United States may be lower than
previously estimated. Am J Gastroenterol 1999;94:183440.
34 Juul KV, stergrd Thomsen O, Nissen A, et al. National surveillance of
Helicobater pylori eradication therapy in Denmark. Results from a
registration of 34,582 prescriptions. Scand J Gastroenterol
1998;33:92832.
193
35 Bytzer P, Teglbjrg PS, Danish Ulcer Study Group. Helicobacter
pylori-negative duodenal ulcers: prevalence, clinical characteristics, and
prognosis-results from a randomized trial with 2-year follow-up. Am J
Gastroenterol 2001;96:140916.
36 Levenstein S. Peptic ulcer at the end of the 20th century: biological and
psychological risk factors. Can J Gastroenterol 1999;13:7539.
37 Friedman GD, Siegelaub MS, Seltzer CC. Cigarettes, alcohol, coffee
and peptic ulcer. N Engl J Med 1974;290:46973.
38 Everhart JE, Kruszon-Moran D, Perez-Peres GI, et al. Seroprevalence
and ethnic differences in Helicobacter pylori infection among adults in
the Unites States. J Infect Dis 2000;181:135963.
39 Chou SP. An examination of the alcohol consumption and peptic ulcer
associationResults of a national survey. Alcohol Clin Exp Res
1994;18:14953.
40 Rosenstock SJ, Jrgensen T, Andersen LP, et al. Association of
Helicobacter pylori infection with lifestyle, chronic disease, body-indices,
and age at menarche in Danish adults. Scand J Public Health
2000;28:3240.
41 Brenner H, Rothenbacher D, Bode G, et al. Inverse graded relation
between alcohol consumption and active infection with Helicobacter
pylori. Am J Epidemiol 1999;149:5716.
42 de Lorimier AA. Alcohol, wine, and health. Am J Surg
2000;180:35761.
43 Weisse ME, Eberly B, Person DA. Wine as a digestive acid: comparative
antimicrobial effects of bismuth salicylate and red and white wine. BMJ
1995;311:165760.
44 Tjnneland AM, Grnbk M, Stripp C, et al. Wine intake and diet in a
random sample of 48,763 Danish men and women. Am J Clin Nutr
1999;69:4954.
www.gutjnl.com
 Downloaded from http://gut.bmj.com/ on June 14, 2015 - Published by group.bmj.com

Risk factors for peptic ulcer disease: a

population based prospective cohort study
comprising 2416 Danish adults
S Rosenstock, T Jrgensen, O Bonnevie and L Andersen

Gut 2003 52: 186-193

doi: 10.1136/gut.52.2.186

Updated information and services can be found at:

http://gut.bmj.com/content/52/2/186

These include:

References This article cites 39 articles, 15 of which you can access for free at:
http://gut.bmj.com/content/52/2/186#BIBL

Email alerting Receive free email alerts when new articles cite this article. Sign up in the
service box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections Ulcer (482)
Campylobacter, Salmonella, Shigella, Escherichia coli (237)
Helicobacter pylori (213)

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/